Frontiers in toxicology最新文献

Background: Snakebite envenoming constitutes a substantial public health concern worldwide. Yunnan Province, The lack of comprehensive epidemiological data on snakebite in Yunnan affects research, diagnostic, and treatment advancements. This research evaluates patient demographics, seasonal patterns, snake species associated with the disease, and treatment approaches to guide preventative and therapeutic initiatives in the province.

Methods: This retrospective analysis reviewed clinical records of venomous snakebite cases admitted to hospitals in 16 cities within Yunnan Province from January 2022 to November 2024. Collected data covered diverse aspects, including patient demographics (age, sex), circumstances of the bite (location, size, and time), species identification, observed clinical symptoms, treatments administered (e.g., antivenin and alternative therapies), and hospital stay duration. Subsequently, the effect of different therapeutic measures on these patients' hospital stays was analyzed.

Results: A total of 2,112 venomous snakebite cases were recorded, with incidence rates rising annually: 406/46.73 million in 2022, 825/46.73 million in 2023, and 886/46.73 million in 2024. Ovophis (52.08%) and Trimeresurus (28.74%) species were predominant. These findings align with the annual distribution of anti-venom serum administered to affected individuals. Most incidents occurred during June to September, primarily in mountainous and forested areas or paddy fields, comprising approximately 52.40% of the total cases. Nearly all bites (99.05%) were localized to the limbs, presenting with swelling and pain as the dominant clinical features. Statistical analysis revealed that factors such as incision and debridement, additional anti-venom serum, fibrinogen supplementation, plasma administration, Ji Desheng Snake Medicine, and magnesium sulfate compresses were significantly associated with extended hospital stays (P < 0.05).

Conclusion: Snake bites in Yunnan Province mainly affect young and middle-aged agricultural workers in rural and mountainous areas. The predominant venomous snakes in the area are hemotoxic. The findings emphasize the necessity of early intervention with antivenom and adjunctive therapies, including fibrinogen and plasma administration. Delays in getting medical help or improper treatment can lead to longer hospital stays.

In chemical risk assessment the human relevance of adverse health effects observed in experimental animal studies and the underlying toxicological mechanisms, i.e., adverse outcome pathways is often assumed, unless evidence suggests otherwise. Yet, detailed systematic guidance as to how human relevance of perturbed AOPs should be assessed and which data or information should be considered is lacking. Building on previous work we present a refined workflow for human relevance assessment of AOPs and associated new approach methodologies The updated workflow structurally defines the required information for assessing the human relevance of the AOP by means of biological and empirical considerations. Furthermore, the modified workflow better guides assessment of the relevance of NAMs. This is of importance for the use of NAM data in human health risk assessment. In addition, we suggest an approach for weight of evidence assessment by integrating the different lines of evidence. The refined workflow is now accompanied by developed guidance and templates as well as an expanded toolbox, i.e., a list of information sources, to further facilitate application of the workflow. Finally, remaining issues and challenges are discussed. This work is a next step towards to the ultimate goal of a harmonized, structured and transparent approach for human relevance assessment of AOPs and associated NAMs.

Introduction: Lamotrigine, a common antiepileptic, typically has a favorable safety profile. However, an overdose can lead to severe central nervous system complications, including refractory status epilepticus. The optimal management of severe overdose with refractory status epilepticus remains uncertain, and the role of extracorporeal removal methods, such as blood purification, has not been fully established.

Case description: A 20-year-old female with bipolar disorder presented with altered consciousness and status epilepticus 7 h after ingestion of 4.9 g of lamotrigine. As a case of lamotrigine intoxication, initial management with gastric lavage, activated charcoal, benzodiazepines, and levetiracetam failed to control the seizures, and the patient required continuous midazolam and ventilation. Slow low-efficiency dialysis (SLED) was initiated 18 h after admission. Lamotrigine levels substantially decreased from 33.9 to 13.5 μg/mL within 5 h post-SLED, representing a 60.2% reduction. The patient showed marked neurological improvement, with seizure cessation, allowing for discontinuation of midazolam. She was extubated on day 4 and discharged on day 7 with full recovery.

Discussion: This case highlights the successful use of SLED in severe lamotrigine overdose-induced refractory status epilepticus. The correlation among SLED use, reduced lamotrigine levels, and clinical improvement suggests that blood purification may be beneficial in severe toxicity, especially in patients with status epilepticus. This adds to the evidence supporting blood purification for accelerated drug removal and improved outcomes in select severe cases. Prompt recognition of this potentially life-threatening condition and consideration of intensive care, including blood purification, are vital for successful management.

Mycotoxins, as feed contaminants, pose serious health risks and cause significant economic losses on farms. The selection of an appropriate and effective adsorbent remains a key challenge for many researchers. Graphene oxide (GO) and its derivatives have garnered interest due to their exceptional physicochemical properties. However, the increasing use of GO necessitates a thorough investigation into its potential toxic impacts on animal and human health, as well as the environment. This study evaluates the effects of GO as a feed additive on calf health. Ten calves (100 ± 6 kg) participated in a 20-day experiment: five in the control group (C) and five in the experimental group (T). The control group (C) received feed without GO, while the experimental group (T) was fed a diet containing 30 g of GO/kg/day. Key parameters evaluated included growth performance, biochemical markers (ALT, AST, ALP), and mineral levels (Ca, P, Mg, K, Na, Cl, Fe, Cu, Zn). The average weight gain was 16.20 ± 0.32 kg in the control group and 15.40 ± 0.26 kg in the GO group, with no statistically significant difference (p > 0.05). Calves fed GO-enriched feed exhibited significant reductions in Fe (p = 0.041) and Zn (p = 0.0006) levels, while Mg increased significantly in the control group (p = 0.029). Liver parameters in group T showed significant increases in ALT (p = 0.022), AST (p = 0.027), and ALP (p = 0.015) after 20 days. Additionally, GPx activity was significantly decreased in the GO group (p = 0.011). These results suggest that GO at a dose of 30 g/kg/day in feed can negatively affect calf health.

Smoking and particulate matter 2.5 (PM2.5) expose millions to cadmium (Cd), a toxic heavy metal linked to pro-inflammatory responses, oxidative stress, and disease pathogenesis. In the oral cavity, chronic Cd exposure contributes to the progression of periodontal diseases and oral cancers. However, the direct effect of Cd on oral tissues and the underlying mechanisms remains unclear. This study explored the impact of environmentally relevant concentrations of Cd on human gingival fibroblasts (HGFs) by evaluating cell viability, pro-inflammatory cytokine secretion (IL-6 and IL-8), COX-2 expression, and the activation of key signaling pathways: Akt, ERK1/2, and JNK. Cd exposure significantly reduced HGF viability, elevated IL-6 and IL-8 secretion, and upregulated COX-2 expression. These effects were attenuated by inhibitors targeting Akt, ERK1/2, and JNK pathways. By integrating cytokine profiling, COX-2 expression, and inhibitor-based pathway analysis, our study provides mechanistic insights into how low-level Cd exposure triggers early inflammatory responses in gingival fibroblasts. Our findings reveal that Cd exerts pro-inflammatory and cytotoxic effects on HGFs, which may play a role as one of the factors in the pathogenesis of smoking-related oral diseases. Targeting Akt, ERK1/2, and JNK signaling pathways could offer therapeutic strategies to attenuate Cd-induced oral pro-inflammatory responses and tissue damage.

Reproductive toxicity is a concern critical to human health and chemical safety assessment. Recently, the U.S. Food and Drug Administration announced plans to assess toxicity with artificial intelligence-based computational models instead of animal studies in "a win-win for public health and ethics." In this study, we used a reproductive toxicity dataset using Simplified Molecular Input Line Entry Specifications (SMILES) to represent 1091 reproductively toxic and 1063 non-toxic small-molecule compounds. A repeated nested cross-validation procedure was applied, in which the dataset was randomly partitioned into five distinct folds in the outer loop, each time, one fold serving as the test set. In the inner loop, a similar procedure was also repeated five times, with 12.5% each time serving as the validation set. We first evaluated the performance of classical machine learning (ML) methods such as Random Forest and Extreme Gradient Boosting on predicting reproductive toxicity, using standard model evaluation metrics including accuracy score (ACC), the area under the curve (AUC) of the receiver operating characteristics curve (ROC) and F1 score. Our analyses indicate that these methods' overall results were mediocre and insufficient for high-throughput screening. To overcome these limitations, we adopted the Communicative Message Passing Neural Network (CMPNN) framework, which incorporates a communicative kernel and a message booster module. Our results show that our ReproTox-CMPNN model outperforms the current best baselines in both embedding quality and predictive accuracy. In independent test sets, ReproTox-CMPNN achieved a mean AUC of 0.946, ACC of 0.857 and F1 score of 0.846, surpassing traditional algorithms to establish itself as a new state-of-the-art model in this field. These findings demonstrate that CMPNN's deep capture of multi-level molecular relationships offers an efficient and reliable computational tool for rapid chemical safety screening and risk assessment.

In research settings, rodents exhibit a well-documented sensitivity to stress-induced behavioral alterations ranging from stereotypy to convulsions. These events complicate preclinical drug safety assessments where establishing a No-Observed-Effect Level (NOEL) requires distinguishing true pharmacologic seizures from stress-related convulsions, including a type lacking electrographic cortical correlates, referred to as psychogenic nonepileptic seizures (PNES). Stress triggers in preclinical settings include environmental factors and systemic conditioning effects of investigational drugs unrelated to seizure risk. Stress-induced behaviors can bias safety assessments by creating false-positive findings of seizure liability incorrectly attributed to the test compound. This paper highlights situations when stress conditioning is present during rodent seizure liability studies and proposes a Weight-of-Evidence (WoE) approach to differentiate between drug-induced ES and stress-conditioned PNES. It supports applying context-specific criteria for regulatory considerations especially when convulsions are absent in higher species, when there are inconsistent findings across facilities, and when rodents present stereotypy and lack of neuropathological evidence of drug-induced seizures. This approach aims to minimize the misinterpretation of stress-related artifacts as true pharmacologic seizures, providing a framework for more reliable and translatable seizure liability assessments.

Introduction: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that accumulate in living organisms, posing significant human health risks. The toxicity mechanisms of PFAS include mitochondrial dysfunction and bioenergetic failure.

Methods: This study evaluates the structure-activity relationship of PFAS compounds with mitochondrial toxicity by comparing the Mito Tox Index (MTI) of perfluoroalkyl carboxylic acids (PFCAs) varying carbon chain lengths. The MTI quantifies the extent to which substances disrupt mitochondrial function by distinguishing between mitochondrial inhibition and uncoupling. This was followed by an assessment of the effect of PFCAs on total cellular bioenergetics and impedance-based real time cell viability measurement.

Results and discussion: Both inhibition and uncoupling MTI values increased with the chain length of PFCAs and severe mitochondrial inhibition was observed when uncoupling was maximized by PFCAs containing seven or more carbons within hours of exposure. The mitochondrial toxicity corresponded well to the bioenergetic failure measured by real-time ATP production rates. In contrast, there was a substantial difference between cytotoxicity and mitochondrial toxicity, despite a common trend of increased toxicity with longer chain lengths. The results suggest that PFCA-induced mitochondrial dysfunction is a key mechanism of PFAS-mediated cellular damage, primarily driven by proton leak-mediated ETC uncoupling, leading to impaired mitochondrial energy production. It also implies that MTI-based mitochondrial toxicity evaluation increases data precision in comparing PFAS effects on mitochondrial function, even identifying the mode of action, which is expected to improve in vitro toxicity prediction models.

Introduction: Type 2 diabetes mellitus (T2DM) is a major global health concern frequently related with chronic low-grade inflammation and a spectrum of cognitive impairments, including deficits in learning and memory. Mercury chloride (HgCl₂), a widespread environmental pollutant, is recognized for its neurotoxic properties and its capacity to trigger inflammatory responses, particularly in patients with metabolic disorders such as T2DM.

Aim: This study aimed to evaluate the subchronic effects of HgCl₂ on cognitive performance and neuroinflammation in a rat model of T2DM, with a particular focus on the roles of BDNF and acetylcholinesterase (AChE).

Materials and methods: The experimental design included four groups: control, HgCl₂-treated, diabetic, and diabetic rats treated with HgCl₂. T2DM was induced by intraperitoneal injections of streptozotocin (STZ) and nicotinamide (NA). Rats in the HgCl₂-exposed groups received an oral dose of 0.375 mg/kg/day for 45 consecutive days. Cognitive performance was assessed using behavioral tests targeting spatial learning, recognition memory, and working memory. Additionally, hippocampal and prefrontal cortex (PFC) levels of TNF-α, IL-6, BDNF, and AChE activity were measured to evaluate neuroinflammatory and neurotoxic responses.

Results: The findings revealed a significant increase in fasting blood glucose levels in both diabetic and HgCl₂-treated diabetic groups compared to controls (P < 0.001). Moreover, HgCl₂ administration in diabetic rats led to a more pronounced impairment in cognitive functions compared to untreated diabetic rats (P < 0.05). These deficits were associated with enhanced neuroinflammatory markers (TNF-α and IL-6), decreased AChE activity, and reduced BDNF expression in the PFC and hippocampus (P < 0.05).

Conclusion: Overall, these results highlight the synergistic impact of hyperglycemia and HgCl₂ exposure in exacerbating neuroinflammation and cognitive decline, suggesting a critical interaction between metabolic and environmental neurotoxic factors.

This paper examines the global communities' regulatory and scientific advancements in nanotechnology and nanomaterials since 2000. It explores some similarities and differences in nanomaterial safety compared to general chemical safety. The paper provides an overview of the encountered challenges and how far they have been resolved, as well as information on how different countries' legislators have addressed nanomaterials, including safety assessment in (new) legislation. Challenges arose due to the unique physico-chemical properties of some nanomaterials and included the lack of i) a regulatory definition, ii) applicable regulatory test methods, including methods for physico-chemical characterization and for ecotoxicological effects, as well as sample preparation and dosimetry, iii) assessment and modelling of human, especially occupational, and environmental exposure to nanomaterials, iv) quantification of nanomaterial in complex media, v) systems for collecting the data generated and ensuring FAIR (Findable, Accessible, Interoperable and Re-usable) and quality data, vi) reference nanomaterials, and vii) a frame for nanotechnology governance. The paper highlights the role of the Organisation for Economic Co-operation and Development (OECD) in building a global, regulatory understanding of nanotechnology and nanomaterials, as well as the OECD's achievements of developing nano-specific test guidelines. The paper identifies areas, such as alternative test methods, availability of reference nanomaterials, comparable data and FAIR data, analytical tools for quantifying nanomaterials in (complex) matrices that are still under-addressed. It gives a wider perspective of Governance of Advanced Materials including nanomaterials, also illustrated by carbon nanotubes used in batteries for electric vehicles, to also aid their commercialization. In the EU, the policy context is moving towards a holistic governance approach embracing sustainability dimensions.